Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells
Language English Country United States Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
23142137
DOI
10.1053/j.gastro.2012.10.048
PII: S0016-5085(12)01607-1
Knihovny.cz E-resources
- MeSH
- Apoptosis MeSH
- Neoplasms, Experimental MeSH
- In Situ Hybridization MeSH
- Immunohistochemistry MeSH
- Colorectal Neoplasms genetics metabolism pathology MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Cell Transformation, Neoplastic genetics metabolism pathology MeSH
- Cell Line, Tumor MeSH
- Neoplastic Stem Cells metabolism pathology MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Cell Proliferation MeSH
- Receptors, G-Protein-Coupled physiology MeSH
- Receptors, Tumor Necrosis Factor physiology MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- RNA, Neoplasm genetics MeSH
- Oligonucleotide Array Sequence Analysis MeSH
- Wnt Signaling Pathway physiology MeSH
- Intestinal Mucosa metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Lgr5 protein, mouse MeSH Browser
- Receptors, G-Protein-Coupled MeSH
- Receptors, Tumor Necrosis Factor MeSH
- RNA, Neoplasm MeSH
- Tnfrsf19 protein, mouse MeSH Browser
BACKGROUND & AIMS: The Wnt signaling pathway is required for maintenance of the intestinal epithelia; blocking this pathway reduces the proliferative capacity of the intestinal stem cells. However, aberrant Wnt signaling leads to intestinal cancer. We investigated the roles of the Wnt pathway in homeostasis of the intestinal epithelium and during malignant transformation in human cells and mice. METHODS: We performed chromatin immunoprecipitation (ChIP) with DNA microarray analysis (ChIP-on-chip) to identify genes regulated by Wnt signaling in human colorectal cancer cells Colo320, DLD1, LS174T, and SW480. Formation of intestinal tumor was induced in C57BL/6J mice using azoxymethane and dextran sulfate. Intestinal tissues from these mice, as well as Apc(+/Min) and Apc(CKO/CKO)/Lgr5-EGFP-IRES-CreERT2 mice, were analyzed by immunohistochemistry and in situ hybridization. RESULTS: We identified promoter regions of 960 genes that interacted with the Wnt pathway nuclear effector T-cell factor 4 in 4 different human colorectal cancer-derived cell lines; 18 of these promoters were present in all chromatin precipitates. Wnt signaling up-regulated a member of the tumor necrosis factor receptor superfamily called TROY. Levels of TROY messenger RNA were increased in human cells with deficiencies in the adenomatous polyposis coli (APC) gene and in cells stimulated with the Wnt3a ligand. Expression of Troy was significantly up-regulated in neoplastic tissues from mice during intestinal tumorigenesis. Lineage tracing experiments revealed that Troy is produced specifically by fast-cycling intestinal stem cells. TROY associated with a unique marker of these cells, leucine-rich repeat-containing G-protein coupled receptor (LGR) 5. In organoids established from the intestinal crypts, Troy suppressed signaling mediated by R-spondin, a Wnt agonist. CONCLUSIONS: TROY is up-regulated in human colorectal cancer cell lines and in intestinal tumors in mice. It functions as a negative modulator of the Wnt pathway in LGR5-positive stem cells.
Central European Biosystems Ltd Vestec u Prahy Czech Republic
Institute for Clinical and Experimental Medicine Prague Czech Republic
Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic
Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic
References provided by Crossref.org
Wnt Effector TCF4 Is Dispensable for Wnt Signaling in Human Cancer Cells
Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells
Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity
